Glucagon receptor antagonist and GIP agonist combination for diet induced obese mice
Laura McShane, Nigel Irwin, D O'Flynn, Zara Franklin, Chandralal Hewage, Finbarr O'Harte
Journal of Endocrinology
Ablation of glucagon receptor signalling represents a potential treatment option for type 2 diabetes (T2DM). Additionally, activation of glucose-dependent insulinotropic polypeptide (GIP) receptor signalling also holds therapeutic promise for T2DM. Therefore, the present study examined both independent and combined metabolic actions of desHis1Pro4Glu9(Lys12PAL)-glucagon (glucagon receptor antagonist) and D-Ala2GIP (GIP receptor agonist), in diet induced obese mice. Glucagon receptor binding has been linked to alpha-helical structure and desHis1Pro4Glu9(Lys12PAL)-glucagon displayed enhanced alpha-helical content compared to native glucagon. In clonal pancreatic BRIN-BD11 beta-cells, desHis1Pro4Glu9(Lys12PAL)-glucagon was devoid of any insulinotropic or cAMP generating actions, and did not impede D-Ala2GIP-mediated (p<0.01 to p<0.001) effects on insulin and cAMP production. Twice daily injection of desHis1Pro4Glu9(Lys12PAL)-glucagon or D-Ala2GIP alone, and in combination, in high fat fed mice failed to affect body weight or energy intake. Circulating blood glucose levels were significantly (p<0.05 to p<0.01) decreased by all treatments regimens, with plasma and pancreatic insulin elevated (p<0.05 to p<0.001) in all mice receiving D-Ala2GIP. Interestingly, plasma glucagon concentrations were decreased (p<0.05) by sustained glucagon inhibition (day 28), but increased (p<0.05) by D-Ala2GIP therapy, with combined treatment resulting in glucagon concentration similar to saline controls. All treatments improved (p<0.01) intraperitoneal and oral glucose tolerance, and peripheral insulin sensitivity. D-Ala2GIP treated mice showed increased glucose-induced insulin secretion in response to intraperitoneal and oral glucose. Metabolic rate and ambulatory locomotor activity were increased (p<0.05 to p<0.001) in all desHis1Pro4Glu9(Lys12PAL)-glucagon treated mice. These studies highlight the potential of glucagon receptor inhibition alone, and in combination with GIP receptor activation, for T2DM treatment.
Circular dichroism, Secondary structure, Ligand binding, Pharmaceutical, Biochemistry